Fibroblast growth factor 21 (
FGF21) as a member of the FGFs serves a key role in
glucose homeostasis and protection of the liver, heart, kidney and skin from damage as well as
cancer cell development. In addition, transcription of
FGF21 is sensitive to diverse damages; however, the role of the transcriptional regulator of
FGF21 in
cancer cells remains to be elucidated. FGFs were identified to have dominant expression in
cancer cells; therefore, mouse forestomach
carcinoma (MFC) cells were used in the present study, which is a mouse
stomach cancer cell strain for identifying the
FGF21 regulators. In promoter analysis of
FGF21, the putative
transcription factor 4 (TCF4) binding motifs (T/AC/GAAAG) were observed within 1.5 kb of the promoter region. Further
chromatin immunoprecipitation and yeast-one hybrid assays identified that TCF4 directly bound to one of the two putative binding motifs observed. A co-immunoprecipitation assay identified that β-
catenin interacts with TCF4 in MFC cells, and the β-
catenin/TCF4 complex bound to the promoter of
FGF21. In order to examine the function of TCF4 and β-
catenin in transcriptional regulation of
FGF21, TCF4 and β-
catenin was transiently expressed in MFC cells. Reverse transcription-quantitative polymerase chain reaction results revealed that overexpression of TCF4 and β-
catenin activated
FGF21 transcription. Besides, suppression of β-
catenin via a specific
short interfering RNA resulted in reduction of
FGF21 expression. Together these findings suggest that the β-
catenin/TCF complex directly activates
FGF21 via promoter binding. The observations of the present study may help elucidate the regulatory mechanism of
FGF21, which is a key pharmaceutical
protein.